Zanubrutinib Demonstrates PFS Benefit Vs Ibrutinib in Relapsed/Refractory CLL/SLL

Zanubrutinib (Brukinsa) produced a superior progression-free survival (PFS) benefit compared with ibrutinib (Imbruvica) in previously treated patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to the final PFS analysis of the phase 3 ALPINE trial (NCT03734016).¹

The PFS benefit was observed in assessments by both an independent review committee (ICR) and investigators. Additionally, zanubrutinib was generally well tolerated, with safety findings at the final PFS analysis consistent with prior reports.

“This positive result adds to the growing body of evidence underpinning our belief in the potential for [zanubrutinib] to provide new hope for [patients with] CLL facing this intractable disease. With this final PFS analysis, [zanubrutinib] has achieved superior PFS, as well as superiority in overall response rate [ORR] vs ibrutinib,” Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology, at BeiGene, stated in a press release. “We look forward to sharing the full results with the medical and patient communities and will submit for presentation at a medical congress and for publication.”

In February 2022, the FDA accepted for review a supplemental new drug application (sNDA) for zanubrutinib for the treatment of adult patients with CLL or SLL.² The sNDA is under review with the FDA, with a target action date of October 22, 2022.

The sNDA is based on previously reported findings from the ALPINE trial, plus data from the phase 3 SEQUOIA trial (NCT03336333). Data from ALPINE presented at the 2022 SOHO Annual Meeting in October showed that the investigator-assessed 12-month PFS rates were 94.9% and 84% in the zanubrutinib and ibrutinib arms, respectively (HR, 0.40; 95% CI, 0.23-0.69; 2-sided P = .0007).³

The randomized, international, open-label ALPINE study investigated zanubrutinib vs ibrutinib in patients who were at least 18 years of age with relapsed/refractory CLL/SLL following at least 1 prior systemic therapy. Patients were required to have measurable lymphadenopathy by CT scan or MRI, and an ECOG performance status between 0 and 2.⁴

Key exclusion criteria included current or past Richter’s transformation, prior treatment with BTK inhibitors, or treatment with vitamin K antagonists, such as warfarin.

Enrolled patients were randomly assigned 1:1 to receive 160 mg of oral zanubrutinib twice daily or 420 mg of oral ibrutinib once daily until disease progression or unacceptable toxicity.

The primary end point of the trial was investigator-assessed ORR, Secondary end points included ICR- and investigator-assessed PFS, duration of response, time to treatment failure, overall survival (OS), patient-reported outcomes, and safety.

Additional data presented at the 2022 SOHO Annual Meeting showed that at a median follow-up of 15 months, patients in the zanubrutinib arm achieved an ORR of 78.3% (95% CI, 72.0%-83.7%) compared with 62.5% (95% CI, 55.5%-69.1%) for patients in the ibrutinib arm (2-sided P = .0006; prespecified α = .0099).3

Furthermore, the 12-month OS rates were 97.0% and 92.7% in the zanubrutinib group and ibrutinib group, respectively (HR, 0.54; 95% CI, 0.23-1.16; 2-sided P = .1081).

Regarding safety, 95.6% and 99.0% of patients in the zanubrutinib and ibrutinib arms, respectively, experienced an adverse effect (AE) of any grade. Grade 3 or higher AEs were reported in 55.9% and 51.2% of the zanubrutinib and ibrutinib arms, respectively. Additionally, 27.5% and 32.4% of the zanubrutinib and ibrutinib arms, respectively, experienced serious AEs, and 3.9% and 5.8% experienced fatal AEs.

In the zanubrutinib arm, 11.3%, 39.7%, and 7.8% of patients experienced AEs that led to dose reduction, dose interruption, and treatment discontinuation, respectively. Those rates were 12.1%, 40.6%, and 13.0%, respectively, in the ibrutinib arm.

References

1. BeiGene announces positive topline results from final progression-free survival analysis of Brukinsa® (zanubrutinib) compared to Imbruvica® (ibrutinib) in phase 3 chronic lymphocytic leukemia (CLL) trial. News release. BeiGene. October 12, 2022. Accessed October 12, 2022. https://bwnews.pr/3yAyaBE
2. BeiGene announces US FDA acceptance of supplemental new drug application for BRUKINSA (zanubrutinib) in chronic lymphocytic leukemia. News release. BeiGene. February 22, 2022. Accessed October 12, 2022. https://bit.ly/3s7MBKx
3. Brown JR, Hillmen P, Eichhorst B, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.
4. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (ALPINE). ClinicalTrials.gov. Updated December 6, 2021. Accessed October 12, 2022. https://clinicaltrials.gov/ct2/show/NCT03734016